Reactivation of varicella-zoster virus (VZV) causes herpes zoster, which is common after bone marrow transplantation and is associated with considerable morbidity and even with life-threatening infection in some patients. The goals are to investigate the immunologic correlates of protection against VZV reactivation after hematopoietic cell transplantation (HCT), the role of viral tropism for human T cells in the pathogenesis of recurrent VZV infections, and the contributions of two novel VZV glycoproteins, gM and gN, to infectivity for T cells and skin. We propose to continue our studies of the reconstitution of VZV immunity by administration of inactivated varicella vaccine in a placebo controlled trial that incorporates a focus on refined analysis of the possible mechanisms and immunologic correlates of protection. The vaccine preparation to be tested will also be of higher initial virus content. The evidence from our current studies is that the inactivated vaccine accelerates reconstitution of VZV specific CD4 T cells in autologous HCT recipients who are vaccinated before as well as after transplant. We will continue to evaluate VZV immune reconstitution using novel assays to quantitate the CD8 as well as CD4 T cell responses in vaccine recipients. Immunologic correlates of protection will be defined by prospective monitoring for VZV-specific memory T cell recovery, and for the occurrence of herpes zoster as well as subclinical VZV reactivations documented by real time polymerase chain reaction (PCR). VZV infects human CD4 and CD8 T cells, which allows transport of the virus to visceral organs; this lymphotropism is an important event in the pathogenesis of VZV infections after HCT since it is responsible for the most serious complications of herpes zoster, such as pneumonia and encephalitis. In viral pathogenesis experiments, we plan to continue our focus on the contributions of VZV glycoproteins. The objective is to use our cosmid approach to generate recombinant VZV strains with modifications or deletions of the newly identified VZV glycoprotein genes, gM and gN. These genes are likely to be dispensable in vitro, but may be manipulated to reduce VZV virulence in vivo, providing a new approach for VZV attenuation. VZV recombinants that have deletions or selected mutations in gM and gN will be evaluated for changes in skin and T cell tropism in vivo in the SCID-hu model. A comprehensive assessment of immunologic correlates of protection from herpes zoster after immunization with inactivated varicella vaccine should suggest ways to enhance the control of VZV reactivation after HCT through targeting restoration of particular host responses; this work should have direct relevance to strategies for optimal reconstitution of host responses to other viral pathogens in high risk patients who have impaired immune function. Better understanding of VZV tropism for T cells and skin, and the contributions of the viral glycoprotein genes to virulence will provide basic information that may allow the design of live attenuated VZV vaccines which are safe and immunogenic in immunocompromised patients.